The peroxidase-cyclooxygenase superfamily of proteins includes the chordata peroxidase subfamily, whose members, myeloperoxidase (MPO), eosinophil peroxidase (EPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO), figure prominently in mammalian biology. In general, these mammalian heme peroxidases catalyze hydrogen peroxide-dependent oxidation of substrates in either one- or two-electron transfers, referred to as peroxidase or halogenation cycles, respectively. Members of the subfamily share structural features, including most importantly the presence of covalent bonds between the heme group and the protein backbone. Mammalian peroxidases exhibit similar biochemical properties but differ with respect to reactions with specific substrates, cellular distribution, and physiologic roles. Two-electron oxidation of halides (Cl−, Br−, I−) or the pseudohalide thiocyanate anion (SCN−) to generate hypohalous acids—namely hypochlorous (HOCl), hypobromous (HOBr), hypoiodous (HOI), and hypothiocyanous (HOSCN)—is the reaction that dominates their participation in mammalian biology. Paired with NADPH oxidase (NOX) protein family members as the source of H2O2, members of the heme peroxidase family participate in a wide variety of biological activities, from host defense to hormone synthesis, and in some cases contribute to the initiation or progression of disease.